Intravenous solutions, such as saline or glucose solutions, are often used as carriers for the continuous administration of drugs to patients at controlled infusion rates. The drugs may be prepackaged in intravenous solution bags or bottles. The drug-containing intravenous solution may be administered by gravity flow, using a drip chamber and rate control valve, or a drop chamber with automatic rate controller. Infusion pumps may also be employed which can be preset to provide a constant solution volume delivery rate, and thereby a selected rate of the drug dissolved in the intravenous solution at a preestablished concentration.
A constant rate drug infusion apparatus, as described above, is not a clinically adequate administration means for drugs where rapid achievement of therapeutic level is needed followed by the maintenance of a highly critical serum level to obtain therapeutic effectiveness over a long period of administration without adverse side effects. Bolus injections of the drug can be used to provide a rapid serum concentration followed by a constant rate infusion, but the transition period between the loading injection and the achievement of a stable serum level at the desired therapeutic concentration is not effectively controlled. A rapid injection followed by a constant slow rate infusion has the disadvantage that there is a considerable time during the early hours when the plasma concentrations are subtherapeutic. A staged infusion has therefore been proposed and used to some extent, a fast constant infusion being used following the loading injection, and then by a slow constant infusion. Multiple further rapid injections may also be used to augment a slow constant infusion. All of these procedures have the disadvantages that they require attention at strictly defined times if the plasma concentration is not to rise to a toxic level or to a level giving undesired side effects, or, on the other hand, to fall to a sub-therapeutic level.
When a drug is administered intravenously the early plasma drug concentrations are much higher than the drug concentrations in tissues with a poor blood supply. With time the drug distributes to these other tissues and a steady state of distribution is reached. Once this distribution in the body has reached steady state, the aim is to maintain the steady state by infusing drug at the same rate at which it is eliminated from the body. It has been known for some time that the ideal infusion regimen to achieve and maintain constant plasma concentrations of a drug is a loading dose followed by an infusion which falls exponentially in concentration to that required to maintain a steady state. See Kruger-Thiemer (1968) Europ. J. of Pharmacology, 4:317. Heretofore, however, there has been no simple practical method of producing this infusion regimen.
The problem of optimized intravenous drug administration has been particularly studied in connection with the infusion of anti-arrhythmic drugs such as lidocaine. The effectiveness of lidocaine depends on the rapid achievement and maintenance of rather narrow therapeutic plasma levels, viz. 1.5 to 5.5 micrograms/milliliter. Concentrations above the critical range have been associated with toxic effects including convulsions, coma, and respiratory arrest, while lower concentrations do not adequately protect the patient against a life-threatening arrhythmia. See Salzer, et al., Clin. Pharmacol. Ther., 29 (5) 617-624 (1981); and Stargel, et al., Amer. Heart J. 102 872-876 (1981). The ideal exponentially decreasing infusion between a loading injection and the constant rate infusion has been approximated by using mechanical constant rate infusion pumps and stepped decreases in the delivery rate. See Vaughn, et al. Europ. J. Clin. Pharmacol. 10, 433-440; and Loo, et al., J. Pharm. Sci., 57, 918-928 (1968).
An additional method using mechanical mixer for achieving an exponentially decreasing delivery has been tested in dogs: Boyes, et al., J. Pharmacol. Exp. Ther. (1970), 174, 1-8. For a similar experimental apparatus, see Foulkes, J. Pharmacol. Exp. Ther. (1965) 150, 406-413. As described in these references, an intravenous solution containing no drug is used for progressive dilution of a solution containing the drug. The solutions were mixed mechanically, viz. by a mixer or magnetic stirrer.
Boyes, et al. pointed out with reference to apparatus for exponentially decreasing infusion of lidocaine that "this is probably not practical in a clinical situation." Clinical Pharmacol. and Therap. (1971) 12: 105-116. Similarly, Tsuei et al, writing about the design of regimens to achieve and maintain a predetermined plasma drug level range, stated that: "The practial difficulties in giving an exponential intravenous infusion preclude the use of these approaches [Bolus dose with exponentially decreasing rate to constant rate] in everyday clinical situations."Clinical Pharm. & Therap. (1980) 28: 289-295, at 291.